The Lower Passaic River (LPR) in New Jersey has been impacted by variety of human activities over the course of the last two centuries. In this risk assessment, we assessed potential human health risks associated with consumption of fish from the LPR, the human exposure pathway of greatest concern when addressing contaminated sediments. Our risk assessment incorporates fish consumption information gathered during a year-long, intercept-style creel angler survey and representative fish tissue concentrations for 156 chemicals of potential concern (COPCs) obtained from USEPA’s public database (OurPassaic website: http://www.ourpassaic.org/projectsites/premis_public/index.cfm?fuseaction=contaminants). Due to the large number of COPCs investigated, this risk assessment was divided into two phases: (1) identification of COPCs that contribute to the majority of overall excess cancer risk and hazard estimates using deterministic and probabilistic methods, and (2) probabilistic characterization of risk using distributions of chemical concentration and cooking loss for those compounds identified in Phase 1. Phase 1 relied on point estimates of COPC concentrations and demonstrated that PCDD/Fs and PCBs (dioxin-like and non-dioxin-like) are the greatest contributors to cancer risk, while non-dioxin-like PCBs are the primary contributors to non-cancer hazard estimates. Total excess cancer risks for adult and child and receptors estimated in Phase 1 were within USEPA’s acceptable excess cancer risk range, with the exception of RME child (3.0 × 10^− 4 and 1.3 × 10^− 4 for deterministic and probabilistic approaches, respectively). Phase 2 focused on PCDD, PCDF, and PCBs and used distributions of chemical concentrations in fish. The results showed that all excess cancer risk estimates were within the acceptable risk range, although non-cancer hazard estimates for PCBs slightly exceeded a Hazard Index of 1. This HHRA of LPR fish ingestion represents the most comprehensive evaluation conducted to date, and demonstrates that measured concentrations of COPCs are not likely to pose a health risk to people who currently consume fish from the LPR.